Nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino) phenylacetic acid and process for their preparation

ABSTRACT

Object of this invention are nitric esters of derivatives of the 2-(2,6-di-halophenylamino)phenylacetic acid, having the following general formula: ##STR1## wherein: A and B are selected from among hydrogen and linear or branched, substituted or non substituted alkyl chains, X is a halogen selected from among chlorine and bromine, Y is selected from among oxygen, NH and NR 1 , wherein R 1  is a linear or branched alkyl group, and n is comprised between 1 and 10 as well as their pharmaceutical utilization and process for their preparation.

This application is a 371 of PCT/EP93/01906, filed Jul. 20, 1993.

This application is a 371 of PCT/EP93/01906, filed Jul. 20, 1993.

TECHNICAL FIELD

Object of the present invention are nitric esters of derivatives of2-(2,6-di-halo-phenylamino)phenylacetic acid, their pharmaceuticalutilization and process for their preparation.

PRIOR ART

The sodium salt of the 2-(2,6-di-chlorophenylamino)phenylacetic acid hasbeen used for a long time in the pharmaceutical field for itsanti-inflammatory activity and has been sold throughout the world formany years. The process for its preparation has been described in theDutch Patent application No. 6.604.752 and in the U.S. Pat. No.3,558,690.

The pharmacological profile and the effectiveness of the sodium salt ofthe 2-(2,6-di-chlorophenylamino)phenylacetic acid are described inAm.J.Med.80, Suppl. 4B, 1-87 (1986), while other data concerning itspharmacological activity as anti-inflammatory agent are reported, forinstance, in C.A.74, 86215 m (1971); Krupp et al. Experimentia 29,450(1973).

The utilization of the 2-(2,6-di-chlorophenylamino)phenylacetic acid asan anti-inflammatory preparation causes, as known, very severe adversereactions, for instance in the gastro-intestinal apparatus, as well asdamages to the liver and the kidneys. There exist numerous experimentalevidences [S.MONCADA, R. M. J.PALMER, E. A.HIGGS, PharmacologicalReviews, 43(2), 109-142 (1991); T. F.LUSHER, C. M.BOULANGER, Y.DOHI,Z.YANG, Hypertension, 19, 117-130 (1992)], on whose basis the integrityof the vasal endothelium is assumed to act as a basically importantprotective barrier to prevent the onset of pathologic reactions invarious organs and apparatuses.

Such protective barrier, and therefore the integrity of the vasalendothelium, is ensured, on the physiological plane, by the presence ofnitric oxide and prostacyclin.

The treatment with drugs having an anti-inflammatory activity, such as,for instance, the sodium salt of the2-(2,6-di-chloro-phenylamino)phenylacetic acid, causes the inhibition ofthe cyclo-oxygenase, an enzyme which governs the synthesis of theprostacyclin precursor. As a consequence, the production of prostacyclinbeing in this way inhibited, the tissular reserve of same is markedlydepauperated, with ensuing compromission of the vasal endothelium.

As said, because of this endothelial damage due to the reduction ofprostacyclin, diffuse pathologic reactions break out which affect thegastrointestinal apparatus, the kidneys and the liver.

OBJECTS OF THE INVENTION

Object of the present invention is to provide a product which, whileensuring the maintenance of the pharmacological activity characteristicof the known anti-inflammatory preparations, can also eliminate theadverse reactions caused by the treatment with said drugs.

Another object of the present invention is the realization of a processfor the preparation of derivatives of the2-(2,6-di-halo-phenylamino)phenylacetic acid having an anti-inflammatoryactivity and that are exempt from those adverse reactions that aretypical of the anti-inflammatory drugs.

DESCRIPTION OF THE INVENTION

These and still other objects and advantages which shall appear from thefollowing description are obtained by derivatives of the2-(2,6-di-halophenylamino)phenylacetic acid, which derivatives,according to the present invention, have the following general formula:##STR2## wherein:

A and B are selected among hydrogen, linear or branched, substituted ornon substituted alkyl chains, X is a halogen selected among chloride andbromine, Y is selected among oxygen, NH, NR₁, wherein R₁ is a linear orbranched alkyl group and n is comprised between 1 and 10.

In fact, it has been observed that the introduction of a group such as aterminal nitric ester in the derivatives of the2-(2,6-di-halo-phenylamino)phenylacetic acid as in (I) permits topreserving the pharmacological activity of anti-inflammatory drugs,while eliminating the adverse reactions caused by the treatment withsaid drugs. The present invention also includes a pharmaceuticalcomposition comprising an effective amount of a derivative2-(2,6-di-halo-phenylamino)phenylacetic acid of formula (I) and aninert, non-toxic, pharmacologically acceptable carrier.

It has also been noticed that the derivatives (I) are useful for thetreatment of different unhealthy conditions, such as for instancerheumatic diseases in general, immunologic disorders, and that they canalso alleviate painful conditions of low-middle severity of any kind.

Besides, the derivatives (I) subject matter of the present invention areuseful in the treatment of the illnesses of the cardiovascular apparatusand in particular in the treatment of myocardial and brain ischemiae, aswell as in cases of arterial thrombosis.

Always according to the present invention, a nitric ester of aderivative of the 2-(2,6-di-halo-phenylamino)phenylacetic acid (I)proved to be especially advantageous, wherein:

A and B are hydrogen, X is chlorine, Y is oxygen, and n is equal tofour, according to the following formula: ##STR3##

Also particularly advantageous according to this invention is a nitricester of a derivative of the 2-(2,6-di-halo-phenylamino)phenylaceticacid (I),

wherein:

A and B are hydrogen, X is chlorine, Y is oxygen, and n is equal to two,according to the following formula: ##STR4##

For the preparation of the derivatives (I) of the2-(2,6-di-halo-phenylamino)phenylacetic acid subject matter of thisinvention, a first process proved to be particularly advantageous which,according to the present invention, comprises the following phases:

Reaction between the sodium salt of the2-(2,6-di-halo-phenylamino)phenylacetic acid or of the 2-(2,6-di-halo-phenylamino)phenylacetic acid functionalized to the carboxylicgroup, and a compound having the following general formula: ##STR5##wherein:

R₄ is selected among chlorine, bromine, NHR in which R is hydrogen orlinear or branched alkyl chain, A and B are selected among hydrogen,linear or branched, substituted or non substituted alkyl chains, R₃ isselected among chlorine, bromine and iodine, and n is comprised between1 and 10, the carboxylic group of the2-(2,6-di-halo-phenylamino)phenylacetic acid being functionalized asacylic chloride, anhydride or the like, obtaining in this way thecorresponding monomer ester or the corresponding amide;

Reaction of said monomer ester or of said corresponding amide with anitrating agent such as AgNO₃ or the like, obtaining in this way nitricesters of derivatives of the 2-(2,6-di-halo-phenylamino)phanylaceticacid (I).

A second process proved also particularly advantageous which, alwaysaccording to the present invention, comprises the following phases:

Reaction between the sodium salt of the2-(2,6-di-halo-phenylamino)phenylacetic acid or of the2-(2,6-di-halo-phenylamino)phenylacetic acid functionalized to thecarboxylic group, with a compound having the following general formula:##STR6## wherein:

R₄ is selected among chlorine, bromine, NHR in which R is hydrogen orlinear or branched alkyl chains, A and B are selected among hydrogen,linear or branched, substituted or non substituted alkyl chains, and nis comprised between 1 and 10, the carboxylic group of the2(2,6-di-halo-phenylamino)phenylacetic acid being functionalized asacylic chloride, anhydride or the like, obtaining in this way either thecorresponding monomer ester or the corresponding amide;

Reaction of said monomer ester or said corresponding amide with anhalogenating compound such as PBr₃ or the like, obtaining in this waysaid monomer ester or said amide, characterized by the presence of aterminal halogen group;

Reaction of said monomer ester or said amide, characterized by thepresence of a terminal halogen group with a nitrating agent such asAgNO₃ or the like, obtaining in this way nitric esters of derivatives ofthe 2-(2,6-di-halo-phenylamino)phenylacetic acid (I). The solvents whichare utilized in the processes subject matter of this invention arepreferably selected among chloroform, methylene chloride, acetonitrile,dimethylformamide, tetrahydrofuran, dioxan and the like.

Such processes for the preparation of derivatives of the2-(2,6-di-halo-phenylamino)phenylacetic acid (I), subject matter of thepresent invention, consist of a limited number of phases, allowing toobtain the products deriving from such processes rapidly, withsatisfactory yields and to high amounts, even on an industrial basis.

According to the processes subject matter of this invention, thepreparation of nitric esters of derivatives of the2-(2,6-di-chloro-phenylamino)phenylacetic acid proved particularlyadvantageous, having the following formulae: ##STR7## which are preparedas described in the following examples, which are given as mereindications that do no limit in any way the protection scope of thisinvention.

EXAMPLE 1

a) 6 g of 1-Br-4-Cl-butane diluted in 250 ml of dimethylformamide weredripped to a solution of 10 g of sodium salt of the2-(2,6-di-chloro-phenylamino)phenylacetic acid in 100 ml ofdimethylformamide. The reaction mix was stirred for 12 hours at roomtemperature, then diluted with water and extracted with methylenechloride. The so extracted organic phase was anhydried on sodium sulfateand the solvent was low-pressure evaporated until 14 g of dry residualwere obtained.

The residual was purified by chromatography on silica gel, utilizingchloroform as eluant system.

The head fractions were then collected, and by low-pressure evaporationof the solvent 11 g of dry residual were obtained and thenchromatographed anew on silica gel, utilizing an eluant mix constitutedby hexane/ether 7/3 (v/v).

The head fractions were collected, the solvent was low-pressureevaporated, and 3 g of 2-(2,6-di-chloro-phenylamino)phenylacetate of4-chlorobutyl (VIII) were obtained.

IR (cm⁻¹): C=0, 1741; NH, 3340. ¹ H-NMR(300 MHz) (CDCl₃): 1.9 ppm(m,4H); 3.6 ppm(m, 2H); 3.85 ppm(s,2H); 4.2 ppm(m, 2H); 6.5-7.45 ppm(m,aromatics).

Mass spectrometry (i.e) : M⁺· 385 b) 1.2 g of AgNO₃ diluted in 11 ml ofacetonitrile were dripped to 2 g of (VIII) obtained as described in a),diluted in 7 ml of acetonitrile. The reaction mix was stirred for 12hours at the temperature of 85° C. and then filtered.

The solvent was low-pressure evaporated from the resulting solution, anda residual was obtained to which 30 ml of methylene chloride were added.The mix so obtained was filtered anew, the organic phase waswater-washed and then anhydried on sodium sulfate. The solvent waslow-pressure evaporated and 2.8 g of dry residual were obtained, whichwere purified thereafter by chromatography on silica gel, utilizing aneluant mix constituted by hexane/ether 7/3 (v/v). The fractionscontaining the product were collected, the solvent was low-pressureevaporated and 2.5 g of nitric ester of2-(2,6-chloro-phenylamino)phenylacetate of 4-hydroxybutyl (II) wereobtained.

IR (cm⁻¹): C=0, 1729; NH, 3322; ONO₂, 1637. ¹ H-NMR(80 MHz) (CDCl₃):1.75 ppm (m, 4H); 3.8 ppm (s, 2H); 4.2 ppm (m, 2H); 4.4 ppm (m, 2H);6.45-7.4 ppm (m, aromatics).

Mass spectrometry (i. e.) M⁺· 412

EXAMPLE 2

a) 0.5 g of ethylester of the 2-(2,6-di-chlorophenylamino)phenylaceticacid were added to 0.5 ml of 4-aminobutanol and the mix so obtained wasstirred at the temperature of 100° C. for 12 hours. The mix was thenbrought again to room temperature, diluted with 5 ml of water andextracted with 5 ml of methylene chloride. The organic phase soextracted was anhydried on sodium sulfate and the solvent waslow-pressure evaporated until 0.19 g of2-(2,6-di-chloro-phenylamino)-4-hydroxylbutyl-phenylacetamide (XII) wereobtained.

IR (cm⁻¹) (nujol): C=0, 1648; NH and OH, 3413. ¹ H-NMR(80 MHz) (CDCl₃):1.65 ppm (m, 4H); 3.3 ppm (m, 2H); 3.6 ppm (m, 2H); 6.08 ppm (m, 1H);6.5 ppm (dd, 1H); 6.85-7.5 ppm (m, 6H).

Mass spectrometry: PM 366

b) 1.14 g of PBr₃ were added to a solution of 0.19 g of2-(2,6-di-chloro-phenylamino)-4-hydroxybutyl-phenylacetamide (XII) in 10ml of chloroform; the mix so obtained was stirred for 30 minutes andthen diluted with 10 ml of water. The organic phase was separated andanhydried on sodium sulfate, and then the solvent was low-pressureevaporated, obtaining in this way a raw residual which was purified bychromatography, utilizing an eluant mix constituted by methylenechloride/ethyl acetate 10/0.1 (v/v).

The intermediate fractions were recovered, the solvent was low-pressureevaporated and 50 mg of2-(2,6-di-chloro-phenylamino)-4-bromobutyl-phenylacetamide (XIII) wereobtained.

¹ H-NMR(80 MHz) (CDCl₃): 1.73 ppm (m, 4H); 3.3 ppm (m, 8H); 3.67 ppm (s,2H); 5.91 ppm (broad s, 1H); 6.5 ppm (dd, 1H); 6.92-7.29 ppm (m, 5H);7.4 ppm (d, 1H).

c) 1.5 g of AgNO₃ diluted in 10.7 ml of acetonitrile were added to asolution constituted by 2.8 g of2-(2,6-di-chloro-phenylamino)-4-bromobutyl-phenylacetamide (XIII)diluted in 9 ml of acetonitrile. The reaction mix was stirred at thetemperature of 25° C. for 3 days and then filtered. The solvent waslow-pressure evaporated from the resulting solution, obtaining in thisway a residual which was purified by chromatography, utilizing methylenechloride as eluant. The fractions containing the product were collected,the solvent was low-pressure evaporated, and 0.5 g of nitric ester of2-(2,6-di-chloro-phenylamino)-4-hydroxybutylphenylacetamide (XI) wereobtained.

IR(cm⁻¹) (nujol): C=0, 1650; NH, 3290; ONO₂, 1630. ¹ H-NMR (80 MHz)(CDCl₃): 1.62 ppm (m, 4H); 3.28 ppm (m, 2H); 4.4 ppm (t, 2H); 5.3 ppm(broad s, 1H); 6.4.9 ppm (dd, 1H); 6.85-7.36 ppm (m, 5H); 7.4 ppm (d,1H).

Mass spectrometry: PM 411.

There has been determined by means of biologic tests, theanti-inflammatory and analgesic activity for instance of derivatives ofthe 2-(2,6-di-halo-phenylamino)phenylacetic acid (I) having thefollowing formulae: ##STR8##

The anti-inflammatory activity of said derivatives of the2-(2,6-di-chloro-phenylamino)phenylacetic acid has been determined inWistar rats, by utilizing the method of the carrageenan edema, asreported in C. A.WINTER, E.RISLEY, G. W.NUSS, Proc. Soc. Exp. Biol.Med.111, 544-547 (1962), while the analgesic activity of said derivativeshas been determined in Swiss mice, as reported by L. C.HENDERSHOT,J.FORSAITH, J.Pharmacol. Exp. Ter. 125, 237-249 (1959).

The anti-inflammatory and analgesic activity of said derivatives isgiven on Table 1, and is expressed as a power ratio relative to2-(2,6-di-chlorophenylamino)phenylacetic acid taken as a reference.

Each value represents a mean of the values obtained by the treatment of10 animals.

The compounds (II) and (XI) utilized for said biological tests weresuspended in 0.5% carboxymethylcellulose before the administration.

                  TABLE 1    ______________________________________                  ANTI-INFLAMM. ANALGESIC    COMPOUND      ACTIVITY      ACTIVITY    ______________________________________    XI            1.25          1.40    II            1.30          1.50    2-(2,6-di-chloro-                  1             1    phenylamino)phenyl-    acetic acid    ______________________________________

Then, the acute toxicity of said derivatives (II) and (XI) was evaluatedby oral administration of a single dose of each compound (II) and (XI),utilizing for each derivative groups of 10 Swiss mice. The lethalityincidence and the onset of toxic symptoms were assessed within a periodof observation of 14 days.

Even upon administration of 250 mg/kg of the compound (II) or thecompound (XI) no apparent toxicity symptoms have been observed in thestudied animals.

Further biological experiments, suitable to determine thepharmacotoxicologic profile of the derivative (II) have been carried outby examining said derivative (II) in comparison with the2-(2,6-di-chlorophenylamino)phenylacetic acid taken as a reference.

A. PHARMACODYNAMIC ACTIVITY Acute Models

RAT CARRAGEENAN PAW EDEMA: the values of ED 30 (mg/kg p.o.) obtained arerespectively equal to 4.88 for the compound (II) and to 4.21 for the2-(2,6-di-chlorophenylamino)phenylacetic acid, showing a comparableeffectiveness between the two compounds.

MOUSE PHENYLQUINONE WRITHING: at doses ranging between 3 and 10 mg/kgp.o., the derivative (II) has shown a full effectiveness and its potencyresulted almost comparable to that of the2-(2,6-di-chlorophenylamino)phenylacetic acid and of indomethacin.

Subacute Models

RAT ADJUVANT ARTHRITIS: the animals treated for 19 consecutive days(from the 3rd to the 21th day after the adjuvant injection) with 3.0mg/kg p.o. of 2-(2,6-di-chloro-phenylamino)phenylacetic acid or with 1.5or 3.0 mg/kg p.o. of the compound (III), have shown a significantreduction of the arthritic symptomatology.

Rat Gastrointestinal Tolerability

In all the animals treated with 15 mg/kg p.o. of2-(2,6-di-chloro-phenilamino)phenylacetic acid, severe diffuseulcerations have been observed; small ulcers have been observed also inanimals treated with 3.5 and 7.0 mg/kg p.o.

The average dose of ulcerogenicity for the2-(2,6-di-chloro-phenylamino)phenylacetic acid has been calculated asbeing equal to 6.1 mg/kg p.o.

The compound (II) showed to be very well tolerated even at much higherdoses compared to the above mentioned ones; small ulcers have beennoticed only in 2 animals out of 10, treated with 100 mg/kg. Thereforeit was impossible to determine the average ulcerogenicity dose for thecompound (II).

General Pharmacology

Secondary pharmacological evaluations of the compound (II) have beencarried out by comparison with the2-(2,6-di-chloro-phenylamino)phenylacetic acid; no additional effectshave been observed besides the primary pharmacological activity on thecentral nervous system, the autonomic system, the cardiovascular,respiratory and gastrointestinal systems.

B. TOXICOLOGY Acute Toxicity in Rodents

Studies have been carried out in two animal species and following twodifferent administration routes.

The following values of LD50 (mg/kg) and of the 95% fiducial limits havebeen obtained: rat, oral route: 511 (356-732); mouse, oral route: 497(323-762); rat, intraperitoneal route: 237 (156-359); mouse,intraperitoneal route: 253 (171-374).

Maximum Tolerated Dose in Non-Rodents

The compound (II) was very well tolerated in this animal species which,as known, is particularly sensitive to this class of compounds.

The animals have been treated with doses increasing from 250 to 1000mg/kg of compound (II): the lowest dose caused no symptomatology, theintermediate dose caused only a reversible diarrhea, while the highestdose caused a severe but reversible diarrhea. On the contrary, theadministration in the same conditions of 10 mg/kg of2-(2,6-di-chloro-phenylamino)phenylacetic acid caused the death of theanimals.

Subacute Toxicity in Rodents

The animals have been treated with 5, 15 and 30 mg/kg of compound (II)for 4 weeks. The general conditions and clinical behaviour, body weightgain, water and food consumption, hematology and clinical chemistry haveshown that the two lowest doses have been well tolerated.

Subacute Toxicity in the Dog

The animals have been treated with 5, 15 and 30 mg/kg of compound (II)for 4 weeks. The general conditions and clinical behaviour, body weightgain, water and food consumption, hematology and clinical chemistry haveshown that the two lowest doses have been well tolerated.

We claim:
 1. Derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid, characterized in that they lave the following general formula: ##STR9## wherein: A and B are selected among hydrogen, linear or branched, substituted or non substituted alkyl chains, X is halogen selected among chlorine and bromine, Y is selected among oxygen, NH, NR₁, wherein R₁ is a linear or branched alkyl group, and n is comprised between 1 and
 10. 2. A derivative of the 2-(2,6-di-halophenylamino)phenylacetic acid according to claim 1, characterized in that X is chlorine, A and B are hydrogen, Y is oxygen and n is equal to
 4. 3. A derivative of the 2-(2,6-di-halophenylamino)phenylacetic acid according to claim 1, characterized in that X is chlorine, A and B are hydrogen, Y is oxygen and n is equal to
 2. 4. A derivative of the 2-(2,6-di-halophenylamino)phenylacetic acid according to claim 1, characterized in that X is chlorine, A and B are hydrogen, Y is NH and n is equal to
 4. 5. A process for the preparation of a derivative of 2-(2,6-di-halo-phenylamino) phenylacetic acid, having the following formula (I): ##STR10## wherein: A and B are selected among hydrogen, linear and branched, substituted and non-substituted alkyl chains, X is halogen selected among chlorine and bromine, Y is selected among oxygen, NH, NR₁, wherein R₁ is a linear or branched alkyl group and n is comprised between 1 and 10, comprising:reaction between the sodium salt of the 2-(2,6-di-halo-phenylamino)phenylacetic acid or of the 2-(2,6-di-halo-phenylamino)phenylacetic acid functionalized to the carboxylic group, with a compound having the following formula (IV): ##STR11## wherein: R₄ is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chain, A and B are selected among hydrogen, linear or branched, substituted or non-substituted alkyl chains, R₃ is selected among chlorine, bromine and iodine, and n is comprised between 1 and 10, the carboxylic group of the 2-(2,6-di-halo-phenylamino)phenylacetic acid being functionalized as acylic chloride, or anhydride, obtaining in this way the corresponding monomer ester or the corresponding amide; reaction of said monomer ester or said amide with a nitrating agent, obtaining in this way nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid (I).
 6. Process for the preparation of a derivative of a 2- ( 2,6-di-halophenylamino)phenylacetic acid, having the following formula (I): ##STR12## wherein: A and B are selected among hydrogen, linear and branched, substituted and non-substituted alkyl chains, X is a halogen selected among chlorine and bromine, Y is selected among oxygen, NH, NR₁, wherein R₁ is a linear or branched alkyl group and n is comprised between 1 and 10, comprising:reaction between the sodium salt of the 2-(2,6-di-halo-phenylamino)phenylacetic acid or of the 2-(2,6-di-halo-phenylamino)phenylacetic acid functionalized carboxylic group, with a compound having the following formula (V): ##STR13## wherein: R₄ is selected among chlorine, bromine, NHR in which R is hydrogen or linear or branched alkyl chain, A and B are selected among hydrogen, linear or branched, substituted or non-substituted alkyl chains, and n is comprised between 1 and 10, the carboxylic group of the 2-(2,6-di-halo-phenylamino)phenylacetic acid being functionalized as acylic chloride, or anhydride, obtaining the corresponding monomer ester or the corresponding amide; reaction of said monomer ester or said amide with a halogenating compound, obtaining in this way said monomer ester or said amide, having a terminal halogen group; reaction of said monomer ester or said amide having a terminal halogen group with a nitrating agent, obtaining in this way nitric esters of derivatives of the 2-(2,6-di-halo-phenylamino)phenylacetic acid (I).
 7. A pharmaceutical composition comprisingan effective therapeutic amount of a derivative of a 2-(2,6-di-halo-phenylamino)phenylacetic acid according to claim 1; and an inert, non-toxic, pharmacologically acceptable carrier.
 8. A therapeutic method for treating rheumatic diseases in a warm-blooded animal comprisingadministering to said warm-blooded animal an effective amount of a derivative of a 2-(2,6-di-halo-phenylamino) phenylacetic acid according to claim
 1. 9. A therapeutic method for treating cardiovascular illnesses in a warm-blooded animal comprisingadministering to said warm-blooded animal an effective amount of a derivative of a 2-(2,6-di-halo-phenylamino) phenylacetic acid according to claim
 1. 10. A therapeutic method for treating miocardial and brain ischemiae in a warm-blooded animal comprisingadministering to said warm-blooded animal an effective amount of a derivative of a 2-(2,6-di-halo-phenylamino) phenylacetic acid according to claim
 1. 11. A therapeutic method for treating arterial thrombosis in a warm-blooded animal comprisingadministering to said warm-blooded animal an effective amount of a derivative of a 2-(2,6-di-halo-phenylamino) phenylacetic acid according to claim
 1. 12. The process as claimed in claim 5,wherein said nitrating agent is AgNO₃.
 13. The process as claimed in claim 6,wherein said halogenating compound is PBr₃.
 14. The process as claimed in claim 6,wherein said nitrating agent is AgNO₃. 